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FREE CE Feline Thyroid Storm: Rapid Recognition to Improve Patient Survival Mary Katherine Tolbert, DVM, DACVIM North Carolina State University Cynthia R. Ward, VMD, PhD, DACVIMa University of Georgia Abstract: In human medicine, thyroid storm is a well-recognized condition of acute thyrotoxicosis in which the patient’s metabolic, thermoregulatory, and cardiovascular mechanisms are overwhelmed by excessive circulating levels of thyroid hormone. The etiology is unknown, but multiple precipitating factors have been proposed. Hyperthyroid cats presenting in thyrotoxic crisis have clinical signs similar to those of human thyroid storm patients; however, thyroid storm has not yet been fully characterized in veterinary medicine. Early recognition and prompt, appropriate treatment of this life-threatening condition are essential to obtaining a favorable outcome. H yperthyroidism is defined as an endocrine disorder characterized by thyroid hyperfunction. Thyrotoxicosis, although often used interchangeably with hyperthyroidism, refers to a clinical spectrum of disease ranging from an uncomplicated syndrome characterized by mild clinical signs to an acute, life-threatening form known as thyroid storm.1–4 Human patients with hyperthyroidism secondary to Graves disease or toxic multinodular goiter may infrequently experience thyroid storm or thyrotoxic crisis.4,5 Rarely, thyroid storm occurs in patients without hyperthyroidism. In veterinary medicine, the syndrome of thyroid storm has yet to be fully described. As hyperthyroidism is a commonly recognized endocrine disorder in cats, hyperthyroid cats are the veterinary patients most likely to present with clinical signs of thyrotoxic crisis or thyroid storm.6 In humans, thyroid storm is defined as organ dysfunction and decompensation secondary to exposure to high concentrations of serum thyroid hormone.3,7 Its exact incidence in human and veterinary medicine is difficult to estimate because no definitive and universally accepted criteria exist for establishing a diagnosis.5,7 The mortality rate among human thyroid storm patients is approximately 30%.3 The mortality rate among feline thyroid storm patients is unknown but may approach similar, if not higher, levels. Recognition of thyroid storm through observation of compatible clinical signs and identification of predisposing factors is critical to reversing this potentially life-threatening syndrome. Physiology a Dr. Ward discloses that she has received financial benefits from Banfield, The Pet Hospital; Morris Animal Foundation; Pfizer Animal Health; and Intervet/Schering-Plough Animal Health. The thyroid hormones, thyroxine (T4, a prohormone) and triiodothyronine (T3), have a wide variety of physiologic effects, including increasing the metabolic rate of most tissues, enhancing the catecholamine response, acting as positive inotropes and chronotropes, exerting catabolic effects on muscle and adipose tissue, and aiding in normal growth and development. The synthesis and secretion of these hormones are controlled by thyroid-stimulating hormone, which is secreted by the ante- Vetlearn.com | December 2010 | Compendium: Continuing Education for Veterinarians® E1 ©Copyright 2010 MediMedia Animal Health. This document is for internal purposes only. Reprinting or posting on an external website without written permission from MMAH is a violation of copyright laws. rior pituitary gland in response to thyrotropin-releasing hormone, which is produced and secreted by the hypothalamus. Although T3 is more potent than T4, most thyroid hormone is secreted in the form of T4. Peripheral monodeiodination controls thyroid hormone effects by converting T4 to T3. Most thyroid hormone (~99%) in the bloodstream is bound to specific T4-binding proteins and is, therefore, metabolically inactive; it becomes unbound before entering cells, where it exerts its effects through nuclear receptor binding. Unbound T3 and T4 suppress the release of thyroid-stimulating and thyrotropinreleasing hormone through negative feedback.3,8 Pathophysiology Although the exact causes of thyroid storm are not yet elucidated, five pathophysiologic mechanisms have been proposed: (1) high circulating levels of thyroid hormones, (2) dramatic changes in thyroid hormone levels, (3) increased cellular sensitivity to thyroid hormones, (4) increased tissue sensitivity to sympathetic activation, and (5) a precipitating event.5,7 Intuitively, high circulating thyroid hormone levels would seem to be an important cause of thyroid storm; however, studies in humans have shown no difference in mean serum T4 concentrations between patients with thyroid storm and those with uncomplicated thyrotoxicosis.1,9 A rapid increase in free thyroid hormone availability, leading to an acute rise in serum thyroid hormone, may prove to play a more important role.1,7,10 Impaired binding affinity and/or decreased binding protein concentration have both been implicated as causes of increased serum levels of free T4 and free T3.9 FELINE PRACTITIONERS AMERICAN ASSOCIATION OF About AAFP The American Association of Feline Practitioners improves the health and well-being of cats by supporting high standards of practice, continuing education, and scientific investigation. Feline practitioners are veterinary professionals who belong to this association because they are “passionate about the care of cats”! American Association of Feline Practitioners 203 Towne Centre Drive Hillsborough, NJ 08844-4693 Telephone: 800-874-0498 or 908-359-9351 | Fax: 908-292-1188 E-mail: [email protected] Media contact: Valerie Creighton, DVM, DABVP E2 Increased sensitivity to thyroid hormone at the cellular level is another factor thought to precipitate thyroid storm.7 Nonthyroidal illnesses characterized by sepsis, hypoxemia, lactic acidosis and ketoacidosis, and hypovolemia have been associated with increased cellular sensitivity to thyroid hormone.5 The pathophysiologic mechanisms are poorly understood but may be associated with decreased thyroid hormone clearance and/or abnormalities associated with nucleic acid receptor binding.1 Additionally, because thyroid storm is similar to a hyperadrenergic state, increased sympathetic activation through interaction between the adrenergic system and excessive circulating thyroid hormone has been suggested as a precipitating event.1,5,7 This theory is supported by the marked improvement often seen in thyroid storm patients after therapeutic blockade of the β-adrenergic system.1,5 Serum and urine catecholamine levels in human patients with thyrotoxicosis have been shown to be within normal limits or even below the reference interval.1,5,7 Although the mechanism is not completely understood, it may be that the excess circulating thyroid hormone does not cause an increase in catecholamine release but rather increases adrenergic receptor expression or intensifies its effects via postreceptor pathways.7 This could result in the signs of adrenergic overstimulation despite normal catecholamine levels. In human medicine, precipitating events have been documented in approximately 98% of cases.5 Known precipitants of thyroid storm include thyroidal and nonthyroidal surgery, infection and other nonthyroidal illness (e.g., diabetic ketoacidosis, trauma, vascular accidents, emotional stress), administration of iodine-containing agents, vigorous palpation of the thyroid, and sudden withdrawal of antithyroid medication.1,5,11 Trauma has been found to predispose patients to thyroid storm through the release of cytokines, leading to activation of the sympathetic nervous system as well as increased free thyroid hormone fractions due to reduced protein binding.12 Clinical Presentation The clinical signs of thyroid storm reflect severe hypermetabolism. In humans, the diagnosis of thyroid storm is based largely on observation of four major categories of clinical signs: (1) central nervous system dysfunction, including agitation, seizures, and coma; (2) fever; (3) gastrointestinal and/ or liver dysfunction; and (4) cardiovascular abnormalities ranging from sinus tachycardia to atrial fibrillation and congestive heart failure.7 Most of the clinical signs associated with thyroid storm resemble those of a hyperadrenergic state. The same clinical signs are observed in human patients with uncomplicated thyrotoxicosis but to a much milder degree.4 Compendium: Continuing Education for Veterinarians® | December 2010 | Vetlearn.com FREE Feline Thyroid Storm CE Feline patients with thyroid storm may have clinical signs similar to those of human thyroid storm patients, including heart disease secondary to increased cardiac output due to increased metabolic demand. Heart disease in these patients is characterized by arrhythmias, murmurs, gallop sounds, vascular accidents, pulmonary edema, or pleural effusion. Additional clinical signs may include neurologic dysfunction, hypertension, acute respiratory distress, dehydration and hypovolemia, gastrointestinal signs, and hypokalemic myopathy, predominantly characterized by extreme weakness and neck ventroflexion.2,13,14 As this syndrome is more frequently recognized in feline patients, the clinical picture will become more defined. Diagnosis The diagnosis of thyroid storm in human patients is often based on a history of hyperthyroidism and compatible clinical signs and/or resolution of clinical signs with appropriate treatment.12 Burch and Wartofsky’s scoring system,1 developed in 1993 as an ancillary diagnostic tool, is used to distinguish human patients with uncomplicated thyrotoxicosis from those with thyroid storm.7 Points are assigned based on the severity of clinical signs. A score of 45 or greater is considered highly suggestive of impending or current thyroid storm. We have created a scoring system based on the Burch and Wartofsky system that may be used to aid in the diagnosis of feline thyroid storm or to anticipate impending storm in at-risk patients (BOX 1). Often, response to treatment may be the only means of obtaining a diagnosis.1,10 Laboratory test results, including routine blood work and measurement of total and free T4, are consistent with hyperthyroidism and cannot be used to distinguish a cat with uncomplicated hyperthyroidism from a cat with thyroid storm. In addition, thyroid function tests are of no value in the veterinary emergency room setting because rapid results are not available. Nonspecific clinicopathologic changes consistent with hyperthyroidism and thyroid storm may include mild erythrocytosis, macrocytosis secondary to increased oxygen-carrying capacity demand, mild hyperglycemia secondary to catecholamine-mediated insulin antagonism, a stress leukogram secondary to increased circulating catecholamines, and mildly elevated liver enzymes, including alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, and aspartate aminotransferase.13,14 Mild to severe hypokalemia may also be noted. Several mechanisms have been proposed for hyperthyroid-induced hypokalemia. Hyperthyroidism can promote potassium losses through the kidneys via decreased proximal tubule reabsorption due to increased renal blood flow and glomerular filtration.13,14 Polyuria associated with hyper- Box 1 Diagnostic Criteria for Thyroid Storm in Catsa Impending or current thyroid storm should be considered if the clinical signs/criteria listed are present for three or more organ systems. Thermoregulatory dysfunction • Temperature >104°F (40°C) Central nervous system effects • Seizure • Coma • Hyperesthesia • Extreme agitation • Ataxia/paresis • Altered mentation Neuromuscular effects • Neck ventroflexion • Lower motor neuron weakness Gastrointestinal-hepatic dysfunction • Diarrhea • Vomiting • Unexplained hyperbilirubinemia Cardiovascular dysfunction • Severe tachycardia • Cardiac arrhythmias • Congestive heart failure • Thromboembolic disease Precipitating cause a Based on the Burch and Wartofsky algorithm for diagnosing human thyroid storm.5 thyroidism also results in renal potassium wasting via losses into the urinary filtrate from the distal nephron.15 Polyuria due to concurrent chronic kidney disease can further exacerbate renal potassium losses in hyperthyroid cats.13,14 Treatment Rapid, aggressive therapeutic intervention (TABLE 1) should be directed toward four main treatment goals: inhibition of the deleterious peripheral effects of thyroid hormones, inhibition of hyperactive thyroid tissue, provision of supportive care, and identification and treatment of precipitating Vetlearn.com | December 2010 | Compendium: Continuing Education for Veterinarians® E3 table 1 Medications for Treating Cats With Thyroid Storm2,13,14,22,23 Drug Dosage/Route Mechanism of Action Antithyroid drugs Methimazole 2.5–5 mg PO, per rectum, or transdermally q12ha Inhibits thyroid hormone synthesis Potassium iodate 25 mg PO q8h Inhibits preformed thyroid hormone release Iopanoic acid 100–200 mg PO q24h Inhibits preformed thyroid hormone synthesis; blocks peripheral conversion of T4 to T3 Inhibition of peripheral effects Propanolol 0.02 mg/kg IV slowly (may repeat up to four times); 2.5–5 mg PO q8–12h Antagonizes hyperadrenergic effects with or without inhibiting peripheral conversion of T4 to T3 Atenolol 1–3 mg/kg PO q12–24h Antagonizes hyperadrenergic effects Esmolol Loading dose: 200–500 μg/kg IV over 1 min; IV CRI: 25–200 μg/kg/min Antagonizes hyperadrenergic effects Dexamethasone sodium phosphate 0.1 mg/kg IV q12–24h Inhibits peripheral conversion of T4 to T3 Potassium gluconate ¼ tsp (2 mEq) per 4.5 kg in food q12h Potassium supplementation Vitamin B12 (B complex) 1 mL IV (in fluids), IM, or SC Vitamin B12 supplementation Low-dose aspirin 5 mg/cat PO q72h Anticoagulation Unfractionated heparin 200–400 U/kg SC q8h until aPTT = 1.5–2 × baseline Anticoagulation Supportive care In patients with normal renal function. aPTT = activated partial thromboplastin time. a causes.1,7 Precipitating causes should be ruled out through a thorough diagnostic evaluation, including a complete blood count, serum chemistry, urinalysis, FeLV/FIV testing, blood pressure measurement, fundic examination, and imaging; other diagnostic tests may also be indicated. in cats is poorly understood and requires further investigation. Propranolol is a nonselective β blocker and, therefore, is contraindicated in cats with asthma or congestive heart failure.13 It has poor bioavailability and requires frequent dosing because of its rapid hepatic metabolism, but it may be beneficial in cases of thyroid storm because it can be Inhibition of Peripheral Effects of Thyroid Hormone administered intravenously.2,18 The mainstay of treatment directed toward the inhibition of Atenolol, a selective β1 blocker, requires only once-daily the peripheral effects of thyroid hormones is β-adrenergic dosing because of enhanced oral bioavailablity,2,13,14 making blockade, unless contraindicated (i.e., in patients with pul- it a more appropriate choice to treat feline thyroid storm. monary disease and/or severe congestive heart failure not A rapid-onset, short-acting β blocker like esmolol may be associated with thyrotoxicosis), because β blockers have a used initially in the emergency setting while monitoring the rapid onset of action and the potential to reverse clinical patient for improvement or deterioration. signs of thyroid storm.16 The actions of β blockers in the treatment of thyroid hyperactivity are poorly understood. Inhibition of Thyroid Hyperactivity Although the thyroid is innervated by sympathetic fibers, β The preferred antithyroid drug, methimazole, is a thionamide blockers do not act directly to inhibit thyroid hormone syn- used to decrease circulating thyroid hormone concentrations by blocking T4 synthesis through inhibition of tyrosine thesis or secretion.17 In humans, propranol is thought to act as a weak inhibitor residue organification.19 Methimazole may be administered of the peripheral conversion of T4 to T3.10 This mechanism orally, rectally, or transdermally. However, it has no effect on E4 Compendium: Continuing Education for Veterinarians® | December 2010 | Vetlearn.com FREE Feline Thyroid Storm CE the amount of preformed thyroid hormone in active thyroid cells.19 Medications that can be used to block the release of preformed thyroid hormone from the thyroid include iodine preparations such as iopanoic acid and potassium iodate.1 Iopanoic acid also inhibits the peripheral conversion of T4 to T3.20 Methimazole should be given 1 hour before administration of iodine preparations because iodine therapy can transiently increase the release of thyroid hormone, resulting in a worsening of the thyrotoxic state.1,5 Supportive Care Supportive care should begin with correction of dehydration along with aggressive potassium and glucose supplementation for hypokalemic and hypoglycemic patients. Cooling fluids should be administered to hyperthermic patients. Blood exchange methods (peritoneal dialysis, plasmapheresis, hemodialysis) have been used in human patients with severe thyroid storm; however, the expense associated with these treatment modalities may make them impractical in veterinary medicine.2 Glucocorticoids are used in human medicine to decrease thyroid hormone release and to inhibit peripheral conversion of T4 to T321; these agents are controversial in veterinary medicine and require further investigation. Identification and Treatment of Precipitating Causes Preventive measures to guard against thyroid storm are important. Because surgery has been reported to be one of the most common precipitating causes of thyroid storm in human patients, pre- and perioperative treatment may be indicated for known hyperthyroid feline patients undergoing surgery.11 A euthyroid state should be ensured before surgery, and the administration of β blockers may prevent the development of thyroid storm postoperatively. Another known precipitant of thyroid storm, abrupt withdrawal of antithyroid medication, may be addressed by the use of a β blocker if methimazole is to be discontinued before iodine 131 (131I ) therapy. After resolution of thyroid storm (if one occurs) and clinical stabilization, 131I therapy may be considered. Conclusion Thyroid storm is a severe, potentially fatal syndrome described in human medicine that is characterized by multiorgan decompensation after exposure to excessive circulating levels of thyroid hormones. While further investigation regarding the prevalence of thyroid storm in hyperthyroid cats presenting on an emergency basis is warranted, hyperthyroid cats may present with signs compatible with thyroid storm. The clinical manifestations of thyroid storm are more Key Points • Thyroid storm is a life-threatening multisystemic disease that may occur in cats with hyperthyroidism. Early recognition and immediate intervention are critical to achieve a successful outcome. • Treatment of thyroid storm is directed toward inhibition of peripheral effects of thyroid hormone, inhibition of hyperactive thyroid tissue, provision of supportive care, and identification and treatment of precipitating causes. readily treatable when recognized early; therefore, rapid recognition and appropriate treatment are mandatory to ensure patient survival. References 1. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am 1993;22(2):263-277. 2. Ward CR. Feline thyroid storm. Vet Clin North Am Small Anim Pract 2007;37(4): 745-754. 3. Pimentel L, Hansen KN. Thyroid disease in the emergency department: a clinical and laboratory review. J Emerg Med 2005;28(2):201-209. 4. Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocr Metab Clin North Am 2006;35:663-686. 5. Sarlis NJ, Gourgiotis L. Thyroid emergencies. Rev Endocr Metab Disord 2003;4(2): 129-136. 6. Greco DS. Endocrine emergencies, part II. Compend Contin Educ Pract Vet 1997; 19(2):23-44. 7. Migneco A, Ojetti V, Testa A, et al. Management of thyrotoxic crisis. Eur Rev Med Pharmacol Sci 2005;9(1):69-74. 8. Boelaert K, Franklyn JA. Thyroid hormone in health and disease. J Endocr 2005; 187(1):1-15. 9. Brooks MH, Waldstein SS, Bronsky D, Sterling K. Serum triiodothyronine concentration in thyroid storm. J Clin Endocrinol Metab 1975;40:339-341. 10.Jao T, Chen Y, Lee H, Tai T. Thyroid storm and ventricular tachycardia. South Med Assoc 2004;97(6):604-607. 11.Hirvonen EA, Niskanen LK, Niskanen MM. Thyroid storm prior to induction of anaesthesia. Anaesthesia 2004;59:1020-1022. 12.Kanbay M, Sengul A, Güvener N. Trauma induced thyroid storm complicated by multiple organ failure. Chin Med J 2005;118(11):963-965. 13.Mooney CT, Thoday KL. CVT update: medical treatment of hyperthyroidism in cats. In: Bonagura JD, ed. Current Veterinary Therapy XIII. Philadelphia: Saunders; 2000:333-337. 14.Mooney CT. Hyperthyroidism. In: Ettinger SJ, Feldman EC, ed. Textbook of Veterinary Internal Medicine. 6th ed. St. Louis: Elsevier Saunders; 2005:1544-1560. 15.Willard MD. Disorders of potassium homeostasis. Vet Clin North Am Small Anim Pract 1989;19(2):241-263. 16.Langley RW, Burch HB. Perioperative management of the thyrotoxic patient. Endocrinol Metab Clin North Am 2003;32(2):519-534. 17.Geffner DL, Hershman JM. Beta-adrenergic blockade for the treatment of hyperthyroidism. Am J Med 1992;93(1):61-68. 18.Jacobs G, Whittem T, Sams R, et al. Pharmacokinetics of propanolol in healthy cats during euthyroid and hyperthyroid states. Am J Vet Res 1997;58(4):398-403. 19.McKeown N, Tews M, Gossain V, Shah S. Hyperthyroidism. Emerg Med Clin North Am 2005;23(3):669-685. 20.Chopra IJ, van Herle AJ, Korenman SG, et al. Use of sodium ipodate in management of hyperthyroidism in subacute thyroiditis. J Clin Endocrinol Metab 1995;80(7): 2178-2180. 21.Franklyn JA, Gammage MD. Treatment of amiodarone-associated thyrotoxicosis. Nat Clin Pract Endocrinol Metab 2007;3(9):662-666. Vetlearn.com | December 2010 | Compendium: Continuing Education for Veterinarians® E5 22.Smith SA, Tobias AH, Jacob KA, et al. Arterial thromboembolism in cats: acute crisis in 127 cases (1992-2001) and long-term management with low-dose aspirin in 24 cases. J Vet Intern Med 2003;17(1):73-83. 23.Maggio F, DeFrancesco TC, Atkins CE, et al. Ocular lesions associated with systemic hypertension in cats: 69 cases (1985-1998). JAVMA 2000;217(5):695-702. 3 CE CREDITS CE Test 1 This article qualifies for 3 contact hours of continuing education credit from the Auburn University College of Veterinary Medicine. Subscribers must take individual CE tests online and get real-time scores at Vetlearn.com. Those who wish to apply this credit to fulfill state relicensure requirements should consult their respective state authorities regarding the applicability of this program. 1. Which statement regarding thyroid storm in human patients is true? a. It is always associated with hyperthyroidism. b. A precipitating event is generally not identified. c. Clinical signs are associated with hypometabolism. d. The clinical signs are the same as for uncomplicated thyrotoxicosis but more severe. 2. ________ is not a treatment option for asthmatic cats with thyroid storm. a. Propanolol b. Methimazole c. Potassium supplementation d. Atenolol 3. Which is not thought to be an underlying mechanism of thyroid storm? a. increased sympathetic activation b. increased sensitivity to thyroid hormone c. rapid increases in free T4 d. decreased conversion of T4 to T3 E6 4. The clinical signs associated with thyroid storm do not include a. gastrointestinal signs. b. fever. c. central nervous system signs. d. upper respiratory signs. 8. Appropriate therapy for thyroid storm does not include a. β blockade. b. β agonists. c. methimazole. d. potassium iodate. 5. Most thyroid hormone in the blood is in the form of a. free T3. b. free T4. c. protein-bound T4. d. protein-bound T3. 9. Measures to prevent thyroid storm might include a. vigorous palpation of the thyroid before 131 I therapy. b. discontinuation of methimazole immediately before surgery. c. administration of atenolol before discontinuing methimazole in preparation for 131I therapy. d. treatment with a β agonist immediately before surgery. 6. Possible precipitating factors for thyroid storm include a. methimazole treatment. b. intravenous fluid therapy. c. trauma. d. β blockade. 7. Diagnostic criteria for thyroid storm include a. appropriate clinical signs. b. hyperthyroidism. c. resolution with appropriate treatment. d. all of the above 10.Impending or current thyroid storm may be diagnosed based on a. the presence of clinical signs in three or more organ systems. b. a history of hyperthyroidism. c. the presence of mild clinical signs. d. a history of recent thyroid surgery. Compendium: Continuing Education for Veterinarians® | December 2010 | Vetlearn.com ©Copyright 2010 MediMedia Animal Health. This document is for internal purposes only. Reprinting or posting on an external website without written permission from MMAH is a violation of copyright laws.